Assuntos
Pesquisa Biomédica/organização & administração , Anormalidades Congênitas , Comportamento Cooperativo , Monitoramento Epidemiológico , Cooperação Internacional , Autoria , Pesquisa Biomédica/métodos , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Anormalidades Congênitas/prevenção & controle , Humanos , América Latina , Modelos Teóricos , Avaliação de Programas e Projetos de SaúdeRESUMO
OBJECTIVE: To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNPs) in candidate genes and population genetic admixture. STUDY DESIGN: Genotyping was performed in 389 families. Maternal, paternal and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males. RESULT: Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; P=0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; P=0.01). Gestational age associated with PTB in PGR rs1942836 at 32-36 weeks (P=0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes. CONCLUSION: This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.
Assuntos
Canais de Potássio Cálcio-Ativados/genética , Nascimento Prematuro/genética , Receptores de Progesterona/genética , Argentina , DNA Mitocondrial , Feminino , Feto , Predisposição Genética para Doença , Genótipo , Humanos , Indígenas Sul-Americanos/genética , Recém-Nascido , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas , População Branca/genéticaRESUMO
Cleft lip/palate is a defect of craniofacial development. In previous reports, chromosome 6q has been suggested as a candidate region for cleft lip/palate. A multipoint posterior probability of linkage analysis of multiplex families from the Philippines attributed an 88% probability of harboring a cleft-susceptibility gene to a narrower region on bands 6q14.2-14.3. We genotyped 2732 individuals from families and unrelated individuals with and without clefts to investigate the existence of possible cleft-susceptibility genes in this region. We found association of PRSS35 and SNAP91 genes with cleft lip/palate in the case-control cohort and in Caucasian families. Haplotype analyses support the individual associations with PRSS35. We found Prss35 expression in the head and palate of mouse embryos at critical stages for palatogenesis, whereas Snap91 was expressed in the adult brain. We provide further evidence of the involvement of chromosome 6q in cleft lip/palate and suggest PRSS35 as a novel candidate gene.
Assuntos
Cromossomos Humanos Par 6 , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Serina Proteases/genética , Animais , Brasil , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Bases de Dados Genéticas , Frequência do Gene , Loci Gênicos , Haplótipos , Humanos , Desequilíbrio de Ligação , Camundongos , Proteínas Monoméricas de Montagem de Clatrina/genética , Palato Duro/embriologia , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , População Branca/genéticaRESUMO
Brazil represents half of South America and one third of Latin America, having more than 186 million inhabitants. After China and India it is the third largest developing country in the world. The wealth is unequally distributed among the states and among the people. Brazil has a large and complex health care system. A Universal Public Health System (SUS: Sistema SPACEnico de Saúde) covers the medical expenses for 80% of the population. The genetic structure of the population is very complex, including a large proportion of tri- hybrid persons, genetic isolates, and a panmictic large majority. Genetic services are offered at 64 genetic centers, half of them public and free. Nationwide networks are operating for inborn errors of metabolism, oncogenetics, and craniofacial anomalies. The Brazilian Society of Medical Genetics (SBGM) has granted 120 board certifications since 1986, and 7 recognized residences in medical genetics are operating in the country. Three main public health actions promoted by the federal government have been undertaken in the last decade, ultimately aimed at the prevention of birth defects. Since 1999, birth defects are reported for all 3 million annual live births, several vaccination strategies aim at the eradication of rubella, and wheat and maize flours are fortified with folic acid. Currently, the government distributes over 2 million US dollars to finance 14 research projects aimed at providing the basis for the adequate prevention and care of genetics disorders through the SUS. Continuity of this proactive attitude of the government in the area of genomics in public health is desired.
Assuntos
Doença/genética , Serviços em Genética/estatística & dados numéricos , Genômica , Planejamento em Saúde , Programas de Rastreamento , Saúde Pública/educação , Saúde Pública/tendências , Brasil , Atenção à Saúde , Política de Saúde , HumanosRESUMO
In this report, we have reanalyzed genotyping data in a collection of families from South America based on maternal origin. Genotyping analysis was performed at the Craniofacial Anomalies Research Center at the University of Iowa. These genotypes were derived from genomic DNA samples obtained from blood spots from children born with isolated orofacial clefts in 45 hospitals located in eight countries (Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Uruguay, and Venezuela) collaborating with ECLAMC (Latin American Collaborative Studies of Congenital Malformations) between January 1998 and December 1999. Dried blood samples were sent by regular mail to the Laboratory of Congenital Malformations, Federal University of Rio de Janeiro. Previous findings suggested that mitochondrial haplotype D is more commonly found among cleft cases born in South America. We hypothesized that association of certain genes may depend upon the ethnic origin, as defined by population-specific markers. Therefore, we tested if markers in MTHFR (5,10-methylenetetrahydrofolate reductase) and RFC1 (reduced folate carrier 1) were associated with oral clefts, depending on the maternal origin defined by the mitochondrial haplotype. Transmission distortion of alleles in MTHFR C677T and RFC1 G80A polymorphic variants was tested in 200 mother/affected child pairs taking into consideration maternal origin. RFC1 variation was over-transmitted to children born with cleft lip only (P = 0.017) carrying mitochondrial DNA haplotypes other than haplotype D. Our results provide a new indication that variation in RFC1 may contribute to cleft lip only. Future studies should investigate the association between oral clefts and RFC1 based on more discrete phenotypes.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/análogos & derivados , Proteínas de Membrana Transportadoras/genética , População Negra , Fenda Labial/etnologia , Fissura Palatina/etnologia , DNA Mitocondrial/genética , Feminino , Ácido Fólico/genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Indígenas Sul-Americanos , Recém-Nascido , Polimorfismo Genético , Proteína Carregadora de Folato Reduzido , América do Sul , População BrancaRESUMO
In this report, we have reanalyzed genotyping data in a collection of families from South America based on maternal origin. Genotyping analysis was performed at the Craniofacial Anomalies Research Center at the University of Iowa. These genotypes were derived from genomic DNA samples obtained from blood spots from children born with isolated orofacial clefts in 45 hospitals located in eight countries (Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Uruguay, and Venezuela) collaborating with ECLAMC (Latin American Collaborative Studies of Congenital Malformations) between January 1998 and December 1999. Dried blood samples were sent by regular mail to the Laboratory of Congenital Malformations, Federal University of Rio de Janeiro. Previous findings suggested that mitochondrial haplotype D is more commonly found among cleft cases born in South America. We hypothesized that association of certain genes may depend upon the ethnic origin, as defined by population-specific markers. Therefore, we tested if markers in MTHFR (5,10-methylenetetrahydrofolate reductase) and RFC1 (reduced folate carrier 1) were associated with oral clefts, depending on the maternal origin defined by the mitochondrial haplotype. Transmission distortion of alleles in MTHFR C677T and RFC1 G80A polymorphic variants was tested in 200 mother/affected child pairs taking into consideration maternal origin. RFC1 variation was over-transmitted to children born with cleft lip only (P = 0.017) carrying mitochondrial DNA haplotypes other than haplotype D. Our results provide a new indication that variation in RFC1 may contribute to cleft lip only. Future studies should investigate the association between oral clefts and RFC1 based on more discrete phenotypes.
Assuntos
Feminino , Humanos , Recém-Nascido , Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/análogos & derivados , Proteínas de Membrana Transportadoras/genética , População Negra , Fenda Labial/etnologia , Fissura Palatina/etnologia , DNA Mitocondrial/genética , População Branca , Ácido Fólico/genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Haplótipos , Indígenas Sul-Americanos , Polimorfismo Genético , América do SulRESUMO
The aim of this work was to search for unequal birth prevalence rates (BPRs) of cleft lip +/- cleft palate (CL/P), and cleft palate only (CPO), among different geographic areas in South America, and to analyze phenotypic characteristics and associated risk factors in each identified cluster. Included were 5,128 CL/P cases, 1,745 CPO cases, and 3,712 controls (like-sexed, non-malformed liveborn infant, born immediately after a malformed one, in the same hospital), over 4,199,630 consecutive births. They were ascertained between 1967 and 2004, in 190 maternity hospitals of the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas) network, in 102 cities of all 10 South American countries. Non-predefined geographical areas with significantly unusual cleft BPRs were identified with Kulldorf and Nagarwalla's spatial scan statistic, employing number of cases and births, and exact location of each hospital. Expected values were cleft BPRs registered for the entire ECLAMC hospital network. Syndromic and non-syndromic clefts were considered for cluster analysis, and phenotypic characterization, while only non-syndromic for risk factor analysis. Seven clusters for CL/P, and four for CPO, with unusual BPRs were identified. CL/P cases in high BPR areas were more severe than elsewhere in the sample, similar to a previous ECLAMC report on microtia. For CL/P, high BPR clusters were associated with high altitude above sea level, Amerindian ancestry, and low socioeconomic strata; low BPR clusters showed association with African Black ancestry. Advanced maternal age, a recognized risk factor for CPO, was also associated with the only identified geographic cluster for CPO.
Assuntos
Fenda Labial/diagnóstico , Fenda Labial/epidemiologia , Fissura Palatina/diagnóstico , Fissura Palatina/epidemiologia , Adulto , Análise por Conglomerados , Feminino , Geografia , Humanos , Lactente , Masculino , Modelos Estatísticos , Razão de Chances , Fenótipo , Prevalência , Fatores de Risco , Fatores Sexuais , América do Sul , SíndromeRESUMO
BACKGROUND: Clefts of the lip and palate are common birth defects, affecting approximately 1 in 700 births worldwide. The aetiology of clefting is complex, with multiple genetic and environmental influences. METHODS: Genotype based linkage disequilibrium analysis was conducted using the family based association test (FBAT) and the likelihood ratio test (LRT). We also carried out direct sequencing of the PVR and PVRL2 candidate genes based on their homology to PVRL1, a gene shown previously to cause Margarita Island clefting. Participants included 434 patients with cleft lip with or without cleft palate or cleft palate only and their mothers from eight countries in South America, 205 nuclear triads (father-mother-affected child) from Iowa, 541 nuclear triads from Denmark, and 100 patients with cleft lip and palate from the Philippines. RESULTS: An allelic variant in the PVR gene showed statistically significant association with both South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including two rare amino acid changes, one in each gene, which were not seen in controls. CONCLUSIONS: We found an association between a common variant in a gene at 19q and isolated clefting in two heterogeneous populations. However, it is unclear from our data if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation.
Assuntos
Cromossomos Humanos Par 19 , Fenda Labial/genética , Fissura Palatina/genética , Alelos , Sequência de Aminoácidos , Moléculas de Adesão Celular , Mapeamento Cromossômico , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Análise Mutacional de DNA , Feminino , Frequência do Gene , Variação Genética , Humanos , Iowa/etnologia , Desequilíbrio de Ligação , Masculino , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Dados de Sequência Molecular , Nectinas , Receptores Virais/genética , Alinhamento de Sequência , América do Sul/etnologiaRESUMO
OBJECTIVES: Determine the model of inheritance of non-syndromic cleft palate in humans. DESIGN: Complex segregation analysis performed in families of consecutive newborns affected with non-syndromic cleft palate. SETTING AND SAMPLE POPULATION: The Latin American Collaborative Study of Congenital Malformations (ECLAMC). Four hundred and seven consecutive newborns affected with non-syndromic cleft palate registered during the period 1967-97. OUTCOME MEASURE: Likelihood ratio test and Akaike information criterion (AIC) values. RESULTS: The single major locus recessive model provided a significantly better explanation of the data. It was the most parsimonious and had the smallest AIC value of the six models tested with approximately the same likelihood as the general model (chi2 = 2.44, p = 0.5). CONCLUSIONS: To have defined a genetic model for non-syndromic cleft palate and provided evidence for a single major locus inheritance suggests that genetic linkage studies could be implemented.
Assuntos
Fissura Palatina/genética , Fissura Palatina/epidemiologia , Feminino , Genes Recessivos , Humanos , Recém-Nascido , Padrões de Herança , Funções Verossimilhança , Modelos Logísticos , Masculino , Modelos Genéticos , Linhagem , América do Sul/epidemiologiaRESUMO
MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.